The N-alkyl-N-trialkylsilylamides are particularly useful as silylating agents in a process for the manufacture of a peptide or peptide analogue. In particular, N-alkyl-N-trialkylsilylamides are useful as silylating agents for amino acids, peptides or peptide analogues in the manufacture of peptides or peptide analogues as e.g. described in EP 2062909 A1 or EP 2060580 A1 or for derivatization of compounds for e.g. gas chromatography as disclosed in U.S. Pat. No. 4,467,037 due to their increased volatility upon silylation.
Different processes for synthesis of N-alkyl-N-trialkylsilylamides are known and summarized e.g. in T. R. Bailey, Science of Synthesis (2005), 21, 811-31. This document discloses the synthesis of 2,2,2-trifluoro-N-methyl-N-(tert-butyldimethylsilyl)acetamide by deprotonating of the amide with NaH at 0° C. followed by treatment with tert-butyldimethylsilyl chloride in a polar aprotic solvent (acetonitrile/benzene 1:1) at 4° C. Further the silylation of N-methylacetamide with trimethylsilyl chloride using triethylamine as nitrogen containing organic base in anhydrous benzene (anhydrous toluene or acetonitrile may be substituted) with the reaction being performed at 0-5° C. is disclosed. The above reactions are explained in more detail in Mahwhinney, T. P.; Madson, M. A., J. Org. Chem., (1982) 47, 3336) and de Benneville, P. L.; Hurwitz, M. J., U.S. Pat. No. 2,876,209, (1959) ; Chem. Abstr., (1959) 53, 67817.
U.S. Pat. No. 4,467,037 relates to the silylation of amino acids for analysis by gas chromatography. One example of this document discloses the reaction of tert-butyldimethylsilyl chloride (1.3 mole) with N-methylacetamide (1 mole) dissolved in triethylamine, which is used as solvent in an amount of about 10 moles. The reaction mixture is stirred for 24 h at room temperature before isolating the end product.
All of these processes of the prior art have in common that solvents are used for dissolving the educts of the reaction, be it for example acetonitrile/benzene 1:1, anhydrous benzene (or anhydrous toluene or acetonitrile) or triethylamine. These solvents have to be removed at some point during the process to isolate the desired product. The use of solvents is always impaired with costs and environmental burden. Furthermore, if the boiling points of the desired product and the employed solvents are not sufficiently distinct a separation by distillation can additionally complicate the isolation of the desired product.
In another approach for the synthesis of N-methyl-N-trimethysilylacetamide EP 0 021 238 directly heats N-methylacetamide with N-trimethylsilylimidazole to boiling at 13 mbar. The temperature of this process is between 120 and 170° C. and the reaction product is continuously removed by distillation over 8 h. The resulting N-methyl-N-trimethylsilylacetamide is subsequently further purified by fractional distillation. This process requires N-trimethylsilylimidazole which is costly, even when imidazole obtained from the process is recovered and the imidazole is again converted into N-trimethylsilylimidazole, for example by means of hexamethyldisilazane. Furthermore, the process requires long reaction times, which is disadvantageous. Besides, it is difficult to carry out a process using such low pressure in an industrial scale and cleaning of the reaction container containing the imidazole obtained from the process is impeded by the high melting point of imidazole (86-90° C.).
There is need for a process for producing N-alkyl-N-trialkylsilylamides which does not have the disadvantages of the prior art. In particular, the process should be economic and environmentally friendly, even on an industrial scale and be able to provide N-alkyl-N-trialkylsilylamides in a good yield and with a sufficient purity using as few steps as possible while keeping low reaction time and low reaction temperatures.
For solving these problems, the present invention provides a process as defined in the claims.